Optimizing Ultrasound Enhanced Delivery of Therapeutics

优化超声增强治疗的输送

• 批准号: 9185490
• 负责人: Flemming Forsberg
• 金额: $ 71.98万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-25 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185490
• 关键词: Academic Medical Centers; Acoustics; Address; Adjuvant; Animals; Biodistribution; Biological; Cancer Etiology; Cell Line; Cessation of life; Clinic; Clinical; Clinical Trials; Contrast Media; Custom; Data; Development; Diagnostic; Disease; Drug Delivery Systems; Eastern Cooperative Oncology Group; Effectiveness; Enrollment; Environment; Equipment; Excision; Goals; Human; Immunohistochemistry; In Vitro; Institutes; Israel; Lead; Leadership; Liver; Malignant neoplasm of pancreas; Mediating; Medical; Methodology; Methods; Microbubbles; Monitor; Multi-Institutional Clinical Trial; Organ; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Protocols documentation; Publishing; Radiation; Research; Research Personnel; Solid Neoplasm; Survival Rate; Systemic Therapy; Techniques; Technology; Therapeutic; Translating; Tumor Volume; Ultrasonography; United States; Universities; University Hospitals; Unresectable; Woman; X-Ray Computed Tomography; abstracting; base; cancer diagnosis; chemotherapy; clinical investigation; clinical practice; contrast enhanced; design; human study; image guided; imaging modality; improved; improved outcome; innovation; men; mouse model; multidisciplinary; new therapeutic target; novel; pre-clinical research; programs; quantitative imaging; quantitative ultrasound; standard of care; tool; treatment response

Abstract Pancreatic cancer is the third most common cancer diagnosed in the United States, with more than 43,000 new cases in 2013. It is the fourth leading cause of cancer-related death in both men and women. Nonetheless, there has been no significant improvement in survival for pancreatic ductal adenocarci- noma (PDAC) patients over the past 30+ years. For this reason, there is a considerable and urgent clinical need to develop innovative strategies for effective drug delivery and treatment monitoring, re- sulting in improved outcomes for patients with PDAC. Our proposal aims at developing contrast-enhanced ultrasound-mediated image-guided drug delivery (CEUS-IGDD) to be that methodology and to translate it from the lab to the clinic. The specific tasks are designed to improve the understanding and methodology for control and monitoring of this IGDD platform, with an initial clinical focus on enhancing the effectiveness of standard chemotherapeutics for treatment of inoperable PDAC. Inherently this project constitutes a multidisciplinary challenge (technological, biological, physical, and medical), and our strategy to address the critical barriers therefore unites an interdisciplinary team of academic and industrial investigators from GE Global Research (GE), Haukeland University Hospital and University of Bergen (together: Bergen), Thomas Jefferson University (TJU), and Rush University Medical Center with more limited efforts by the Israel Institute of Technology and GlaxoSmithKline (GSK). Aim 1 will develop tools and methods to ascertain optimal conditions (acoustic regime, bubble type) for maximum drug delivery with minimal application of diagnostic-range acoustic energy. Aim 2 utilizes two com- plementary established pancreatic adenocarcinoma mouse models, using human MIA PaCa-2luc (Bergen) and PANC-1 (TJU) cell lines. The efficacy of CEUS-IGDD will be evaluated using biodistribution data and quan- titative imaging methods to monitor treatment response expecting a greater median survival of at least 5 days and a median tumor volume reduction of 50% in the treated group compared to animals receiving drug alone. The main focus of this proposal is Aim 3, where a three year, multi-center clinical trial en- rolling one hundred and twenty (120) patients with metastatic or locally advanced and surgically unresectable PDAC will be conducted at TJU and Bergen. All patients will undergo standard of care chemotherapy, with one-half receiving adjunctive CEUS-IGDD. Patient outcomes will be compared by quantitative ultrasound as- sessment, CT imaging including RECIST criteria, ECOG grade, and immunohistochemistry to assess local progression-free and overall survival with the main endpoint being to increase the number of chemo- therapy cycles by 75% in the IGDD group relative to controls.

抽象的 胰腺癌是美国诊断出的第三大癌症，超过 2013年有43,000例新病例。这是男性和女性与癌症相关死亡的第四个主要原因。 尽管如此，胰腺导管腺癌的生存尚无显着改善 在过去30多年中，Noma（PDAC）患者。因此，有一个相当紧迫的 临床需要制定创新策略，以进行有效的药物输送和治疗监测，重新 PDAC患者的预后改善。我们的建议旨在发展对比增强 超声介导的图像引导的药物输送（CEUS-IGDD）是该方法，并将其转化为 实验室到诊所。特定任务旨在改善控制的理解和方法 并监视此IGDD平台，最初的临床重点是增强标准的有效性 化学治疗药物用于治疗无法使用的PDAC。 本质上，这个项目构成了多学科的挑战（技术，生物学，物理和 医疗），以及我们解决关键障碍的战略，因此团结了一个学术的跨学科团队 以及GE Global Research（GE），Haukeland大学医院和大学的工业研究人员 卑尔根（一起：卑尔根），托马斯·杰斐逊大学（TJU）和拉什大学医学中心 以色列技术与葛兰素史克林研究所（GSK）更有限的努力。 AIM 1将开发工具和方法，以确定最佳条件（声学，气泡类型） 最大程度地递送药物，最少应用诊断范围的声能。 AIM 2使用两个com- 使用人MIA PACA-2LUC（卑鄙）和 PANC-1（TJU）细胞系。 CEUS-IGDD的功效将使用生物分布数据和quan-评估 指导治疗反应的代数成像方法，预期中位生存率至少为5个 与接受的动物相比 独自吸毒。该提案的主要重点是AIM 3，其中三年的多中心临床试验进入 滚动一百二十（120）个转移性或局部晚期和手术无法切除的患者 PDAC将在TJU和卑尔根进行。所有患者将接受护理化疗标准，并具有 一半接收辅助CEUS-IGDD。将通过定量超声AS-比较患者的预后 安排，CT成像，包括恢复标准，ECOG等级和免疫组织化学，以评估局部 无进展和整体存活率，主要终点是增加化学的数量 相对于对照组，IGDD组的治疗周期为75％。